PROJECTSUMMARY Persistentshoulderpain,stiffnessandweaknessarecommonsymptomsofchronicrotatorcuff(RC)tearsthat limitfunctionanddecreasequalityoflifefor>10%ofthepopulationoverage60.DegenerationofRCmuscles, particularly the accumulation of fat within and around these muscles, is thought to be linked to persistent shoulderdysfunction,butthenatureofthislinkremainsundefined.Thelong-termobjectiveofthisresearchis to understand the role of fat-muscle crosstalk on the processes of muscle degeneration and regeneration. Currently, the accumulation of RC fat is thought to be an irreversible feature of chronic RC tears that contributestopoorsurgicalandrehabilitativeoutcomes.Webelieve,however,thattheuniquepropertiesofRC fat make it a novel therapeutic target to promote, rather than inhibit, muscle functional recovery. Specifically, RC fat has a beige phenotype that may be stimulated to take on some properties of brown fat, such as the local secretion of anabolic factors. Accordingly, for this application, our primary objective is to elucidate the cellular targets and downstream effects of phenotype-specific fat-muscle cross-talk in the injured rotator cuff. Ourcentralhypothesisisthatanabolicsignalingfrombrownfatmitigatesmuscleatrophyandpromotesmuscle hypertrophy. To address our hypothesis, our approach will be to adapt models of RC injury and repair to includetransplantofknownfatphenotypes(brown,beigeandwhite)andquantifythedownstreameffectson musclesize,strengthandintracellularsignaling.Specifically,Aim#1willidentifytheeffectsofRCfat-muscle cross-talkonatrophicchangesinanexperimentalmodelofRCtearandAim#2willdeterminethepotentialfor brownfattopromotemusclehypertrophyfollowingrepairofthetear.Altogether,thesestudieswillbroadenour understanding of the contribution of RC fat accumulation to muscle pathology and the nature of fat-muscle crosstalkingeneral.Ultimately,weexpectthiswillhaveasignificantimpactonthedevelopmentoftreatment strategies designed to target fat accumulation, not only in the RC but also in other conditions such as aging andtype2diabeteswherefataccumulationisthoughttoimpactmusclefunction.